Several types of effector cells have surface receptors that bind the Fc portion of immunoglobulin (IgG). When such cells (monocytes, granulocytes, K cells, etc.) encounter target cells that have been opsonized with IgG antibodies, they form conjugates with the target cells. Subsequently, the effector cells either lyse or phagocytose the target cells, depending upon the effector cell type, the target cell type and the specific Fc receptor type involved.
Two distinct classes of IgG Fc receptors (FcR) have been identified on human monocytes and on the human monocytic cell line U937. Looney, R.J., et al., (1986) J. Immunol. 136:1641-1647. One is a 72kDa sialoglycoprotein (p72) with high affinity (Ka=10.sup.8 -10.sup.9 M-1) for monomeric human IgG1 and IgG3 and for murine subclasses IgG2a and IgG3. Alexander, M.D., et al. (1978) Immunol. 35:115-123; Anderson, C.L. and Abraham, G.N. (1980) J. Immunol. 125:2735-2741; Lubeck, M.D. et al. (1985) J. Immuno. 135: 1299-1304. The other receptor is a 40kDa molecule (p40) which shows relatively low affinity for monomeric IgG. Looney, et al., supra; Jones, D.H., et al. (1985) J. Immunol. 135:33483353. P40 has been defined by its ability both to form rosettes with erythrocytes coated with murine IgG1 and to bind aggregated murine IgG2b at low ionic strength. In addition, a monoclonal antibody (IV3) has been prepared which binds to the 40kDa receptor and inhibits ligand binding. See Looney, R.J., et al., supra. This receptor is present not only on mononuclear phagocytes but on human platelets, neutrophils and eosinophils. Rosenfeld, S.I., et al. (1985) J. Clin. Invest. 76:2317-2322.
These two Fc receptors on human monocytes have been shown to mediate anti-T3-induced human T cell mitogenesis by distinct subclasses of murine IgG. The 72kDa FcR mediates murine IgG2a anti-T3-induced stimulation whereas the 40kDa FcR mediates murine IgG1 anti-T3-induced T cell mitogenesis. See Looney et al., supra. Based upon their distinctive affinities for murine IgG subclasses, p72 and p40 are thought to be the human homologues of murine macrophage FcRI and FcRII specific for murine IgG2a and IgG2b/1, respectively. Although not present on monocytes or U937 cells, a third class of IgG FcRs has been described on human neutrophils and null cells.
It has been demonstrated that target cell conjugation and lysis can also be induced by covalently cross-linked heteroantibody made up of both anti-Fc receptor antibody and antibody directed against a target cell epitope. When effector cells bind such heteroaggregates to their Fc receptor, they can specifically bind and lyse target cells which have not been opsonized, but which express the appropriate target antigen. Segal et al. have recently reported cytolysis of tumor cells by mouse monocytes with an attached heteroantibody which joins the Fc receptor of the monocyte on one end with tumor cell epitopes on the other end. The targeting of effector cells with conventional heteroantibodies, however, is likely to be only marginally effective in vivo because the binding of antibody to Fc receptors can be blocked by physiological concentrations of IgG.